Magnetic resonance imaging is a diagnostic technique that has become particularly attractive to physicians as it is non-invasive and does not involve exposing the patient under study to potentially harmful radiation such as X-rays.
In order to achieve effective contrast between MR images of different tissue types, it has long been known to administer to the subject MR contrast agents (e.g. paramagnetic metal species) which affect relaxation times in the zones in which they are administered or at which they congregate. MR signal strength is dependent on the population difference between the nuclear spin states of the imaging nuclei. This is governed by a Boltzmann distribution and is dependent on temperature and magnetic field strength. Techniques have been developed which involve-ex vivo nuclear spin polarisation of agents containing non zero nuclear spin nuclei (e.g. 3He), prior to administration and MR signal measurement. Some such techniques involve the use of polarising agents, for example conventional OMRI contrast agents or hyperpolarised gases to achieve ex vivo nuclear spin polarisation of non zero nuclear spin nuclei in an administrable MR imaging agent. By polarising agent is meant any agent suitable for performing ex vivo polarisation of an MR imaging agent.
The ex vivo method has the advantage that it is possible to avoid administering the whole of, or substantially the whole of, the polarising agent to the sample under investigation, whilst still achieving the desired nuclear spin polarisation in the MR imaging agent. Thus the method is less constrained by physiological factors such as the constraints imposed by the administrability, biodegradability and toxicity of OMRI contrast agents in in vivo techniques.
MRI methods involving ex vivo nuclear spin polarisation may be improved by using nuclear.spin polarised MR imaging agents comprising in their molecular structure nuclei capable of emitting MR signals in a uniform magnetic field (e.g. MR imaging nuclei such as 13C or 15 N nuclei) and capable of exhibiting a long T1 relaxation time, and preferably additionally a long T2 relaxation time. Such agents are referred to hereinafter as “high T1 agents”. A high T1 agent, a term which does not include 1H2O, will generally be water-soluble and have a T1 value of at least 6 seconds in D2O at 37° C. and at a field of 7T, preferably 8 secs or more, more preferably 10 secs or more, especially preferably 15 secs or more, more especially preferably 30 sees or more, yet more especially preferably 70 secs or more, even yet more especially preferably 100 secs or more. Unless the MR imaging nucleus is the naturally most abundant isotope, the molecules of a high T1 agent will preferably contain the MR imaging nucleus in an amount greater than its natural isotopic abundance (i.e. the agent will be,enriched” with said nuclei).
The use of hyperpolarised MR contrast agents in MR investigations such as MR imaging has the advantage over conventional MR techniques in that the nuclear polarisation to which the MR signal strength is proportional is essentially independent of the magnetic field strength in the.MR apparatus. Currently the highest obtainable field strengths in MR imaging apparatus are about 8T, while clinical MR imaging apparatus are available with field strengths of about 0.2 to 1.5T. Since superconducting magnets and complex magnet construction are required for large cavity high field strength magnets, these are expensive. Using a hyperpolarised contrast agent, since the field strength is less critical it is possible to make images at all field strengths from earth field (40-50 μT) up to the highest achievable fields. However there are no particular advantages to using the very high field strengths where noise from the patient begins to dominate over electronic noise (generally at field strengths where the resonance frequency of the imaging nucleus is 1 to 20 MHz) and accordingly the use of hyperpolarised “contrast agents opens the possibility of high performance imaging using low cost, low field strength magnets.
As has been demonstrated previously (see for example the present Applicant's own earlier International Publication No. WO-A-99/35508, the disclosure of which is hereby incorporated by reference) it is possible to hyperpolarise compounds comprising long T1 nuclei, e.g. 13C or 15N nuclei, in order to produce injectable contrast agents. For example, it is possible to use the ‘para-hydrogen method’—see Applicant's own earlier International Publication No. WO-A-99/24080—or dynamic nuclear polarisation (DNP) see WO-A-99/35508.
one problem with these previously described techniques is that whilst the value of the gyromagnetic ratio, γ, for hydrogen is 42.6 MHz/T, it is much lower for both carbon and nitrogen, at 10.7 MHz/T and 4.3 MHz/T, respectively. However, the signal-to-noise ratio of images generated by MRI is, to a first approximation, linearly dependent on the value of the gyromagnetic ratio of the imaged nucleus. Therefore, assuming that the concentration of the contrast medium and the degree of polarisation are equal, images generated using a 13C or more especially a 15N-based contrast medium will have significantly lower signal-to-noise ratios than those images generated using a 1H-based contrast medium.
A further drawback in using 13C or 15N-based contrast medium, particularly in angiography, relates to the gradient power that is required for the MRI. This is due to the fact that the required gradient is inversely dependent upon the value of the gyromagnetic ratio of the imaged nucleus. Thus, in the case of 13C_ or 15N-based contrast media with relatively low gyromagnetic ratio values, correspondingly high gradients are required. Such inverse proportionality between gradient and the value of the gyromagnetic ratio of the imaged nucleus means 13C that -based imaging must be performed using gradients approximately four times that required for a given pulse sequence used in 'H-based imaging. Furthermore, when 15N-based imaging is required, the gradient needs to be approximately 10 times that required for 1H-based imaging.
At present, in 1H-based angiography, the maximum available gradient amplitudes are used in order to suppress phase artifacts.
Thus, if hyperpolarised contrast media containing non-proton imaging nuclei, particularly 13C or 15N nuclei, are to be used in combination with fast imaging sequences, there will be a less than optimal image quality, due to the lower values of the gyromagnetic ratio of the non-proton imaging nuclei.
Furthermore, a problem in using nuclei with relatively high gyromagnetic ratios in ex vivo polarisation techniques is that such nuclei have comparatively short T1 values. Therefore, it is possible to alleviate such problems by employing nuclei with relatively low gyromagnetic ratios in the ex vivo polarisation step and utilising a pulse sequence to transfer polarisation from the nuclei with relatively low gyromagnetic ratios to nuclei with relatively high gyromagnetic ratios.